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About Amarin

AMARIN - GUIDED BY SCIENCE; DRIVEN TO HELP IMPROVE PATIENT CARE

Amarin Corporation plc. is a rapidly growing, innovative biopharmaceutical company focused on developing therapeutics to improve cardiovascular health. Amarin’s product development program leverages its extensive experience in lipid science and the potential therapeutic benefits of polyunsaturated fatty acids. This focus includes a commitment to research and education in cardiovascular health.

High levels of quality, integrity and collaboration are embedded in Amarin’s culture. Amarin, through its dedicated team of professionals, constantly seeks to improve patient care through its actions and products while also striving to continuously improve along the way. By working together and supporting these efforts, inside and outside of the company, Amarin can empower, share and learn as it strides toward the unified goal of excellence—and beyond.

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The Food and Drug Administration (FDA) has not reviewed and opined on a supplemental new drug application related to REDUCE‑IT. FDA has thus not reviewed the information herein or determined whether to approve VASCEPA for use to reduce the risk of major adverse cardiovascular events in the REDUCE-IT patient population.

Important Safety Information for VASCEPA from FDA-Approved Label

Data from Two 12-Week Studies (MARINE and ANCHOR) of Patients with Triglycerides Values of 200 to 2000 mg/dL (n=622 on VASCEPA, n=309 on placebo)1

VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components

In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy

Use with caution in patients with known hypersensitivity to fish and/or shellfish

The most common reported adverse reaction (incidence >2% and greater than placebo) was arthralgia (2.3% VASCEPA, 1.0% placebo)

Adverse events may be reported by calling 1-855-VASCEPA or the FDA at 1-800-FDA-1088

IMPORTANT INFORMATION FOR HCPs ABOUT VASCEPA® (ICOSAPENT ETHYL) CAPSULES

IMPORTANT NEW INFORMATION: REDUCE-IT™ CARDIOVASCULAR OUTCOMES STUDY OF VASCEPA®2,3*

The effects of VASCEPA on the prevention of cardiovascular (CV) events was evaluated in a multi-center, double-blind, randomized, placebo-controlled, event-driven trial (REDUCE-IT, NCT01492361) in 8,179 adult patients enrolled in 11 countries, with a median baseline low-density lipoprotein cholesterol (LDL-C) level of 75 mg/dL, with established cardiovascular disease (CVD) or at high risk for CVD, and hypertriglyceridemia (fasting triglycerides (TG) ≥135 and <500 mg/dL).

Patients were eligible to enter the trial if they were at least 45 years of age and on stable statin therapy with fasting LDL-C levels of >40 and ≤100 mg/dL and fasting TG levels of ≥135 and <500 mg/dL. Patients also needed to have either established CVD (secondary prevention cohort), defined as documented history of coronary artery disease, cerebrovascular or carotid disease, or peripheral artery disease, or be at least 50 years of age with diabetes and at least one additional risk factor (primary prevention cohort).

Patients enrolled were stabilized on statin therapy prior to baseline with most (93.2%) on a high- (30.8%) or moderate-intensity (62.5%) statin therapy, and 6.4% were also taking ezetimibe at baseline.

The primary results from REDUCE-IT are shown in the Table below (seeCONDUCT OF REDUCE-IT AND ANALYSIS AND REVIEW OF REDUCE-IT DATA).

Effect of VASCEPA on CV Events in Patients with Established CVD or at High Risk for CVD with Statin-treated Triglycerides ≥135 and <500 mg/dL in REDUCE-IT

VASCEPA significantly reduced the following:

the risk for the primary composite endpoint (5-point MACE: time to first occurrence of CV death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization; p<0.001), and

the key secondary composite endpoint (3-point MACE: time to first occurrence of CV death, myocardial infarction, or stroke; p<0.001).

Prespecified hierarchical testing of other secondary endpoints revealed significant reductions in the following:

CV death (p=0.03),

fatal or nonfatal myocardial infarction (p<0.001),

fatal or nonfatal stroke (p=0.01),

emergent or urgent coronary revascularization (p<0.001), and

hospitalization for unstable angina (p=0.002).

The benefits of VASCEPA were seen on a background of predominately (93.2%) moderate- to high-intensity statin use and median baseline LDL-C levels of 75.0 mg/dL.

The Kaplan-Meier estimates of the cumulative incidence of the primary and key secondary composite endpoints over time are shown in Figure 1 and Figure 2 below.

ARR = absolute risk reduction, CI = confidence interval, HR = hazard ratio, NNT = number needed to treat, RRR = relative risk reduction. Curves were visually truncated at 5.7 years due to a limited number of events beyond that point in time; all patient data were included in analyses.

ARR = absolute risk reduction, CI = confidence interval, HR = hazard ratio, NNT = number needed to treat, RRR = relative risk reduction. Curves were visually truncated at 5.7 years due to a limited number of events beyond that point in time; all patient data were included in analyses.

The difference between VASCEPA and placebo in median percent change in TG from baseline to Month 4 was -20.1 (p<0.001) and from baseline to Month 12 was -19.7 (p<0.001). At Month 12, the median [Q1, Q3] TG was 175.0 [132.0, 238.0] mg/dL in the VASCEPA group, with 35.9% of patients having TG <150 mg/dL and 61.3% having a TG <200 mg/dL. The difference between VASCEPA and placebo in median percent change in LDL-C from baseline to Month 12 was -6.6% (p<0.001). At Month 12, the median [Q1, Q3] LDL-C was 77.0 [63.0, 94.0] mg/dL in the VASCEPA group, with 35.5% of patients having LDL-C <70 mg/dL and 79.9% having LDL-C <100 mg/dL.

Important Safety Information for VASCEPA from REDUCE-IT (n=4089 on VASCEPA, n=4090 on placebo)

Patients were exposed to VASCEPA or placebo for a median of 52 months; 86.9% of patients were exposed for ≥ 12 months, 77.2% were exposed for ≥ 24 months, 64.6% were exposed for ≥ 36 months, 53.6% were exposed for ≥48 months, 29.5% were exposed for ≥ 60 months, and 0.1% were exposed for ≥72 months.

Overall adverse event (AE) rates were similar across treatment groups.

Adverse events (AE) and serious adverse event (SAE) rates leading to study drug discontinuation were similar to placebo.

A single serious adverse event (SAE) occurred at a frequency of at least 2%, which was pneumonia (2.6% in the VASCEPA group and 2.9% in the placebo group, p=0.42)

Treatment-Emergent Adverse Events

Adverse events (AE) occurring in ≥5% of VASCEPA patients and statistically more frequently with VASCEPA than placebo:

Peripheral edema (6.5% VASCEPA patients versus 5.0% placebo patients)

There was no significant difference in the prespecified adjudicated tertiary endpoints of new congestive heart failure which occurred in 4.1% of VASCEPA patients versus 4.3% of placebo patients, or in new heart failure requiring hospitalization, which occurred in 3.4% of VASCEPA and 3.5% of placebo patients.

This adverse event (AE) finding is consistent with an increase in the prespecified adjudicated tertiary endpoint of atrial fibrillation or flutter requiring hospitalization, which occurred in 3.1% of VASCEPA patients versus 2.1% of placebo patients (p=0.004).

A limitation of the REDUCE-IT cardiovascular outcomes trial is that it was not designed to evaluate whether VASCEPA contributed to an increase in atrial fibrillation or flutter, or whether VASCEPA prevented patients who would have otherwise have had atrial fibrillation or flutter from having another major adverse cardiovascular event such as cardiac arrest or sudden cardiac death.

Importantly, there was no increase in stroke, the most serious atrial fibrillation-related complication, but rather a statistically significant 28% reduction with VASCEPA versus placebo (p=0.01). Significant and substantial reductions were also observed in the secondary and tertiary endpoints of myocardial infarction (31%), cardiac arrest (48%), and sudden cardiac death (31%) with VASCEPA versus placebo.

Among patients with atrial fibrillation/flutter hospitalization endpoints while in REDUCE-IT, rates were similar for stroke (3.1% with VASCEPA versus 7.1% with placebo; p=0.20), new anticoagulant therapy (64.6% with VASCEPA versus 63.1% with placebo; p=0.88), and serious bleeding (8.7% with VASCEPA versus 6.0% with placebo; p=0.60).

In 751 patients with a baseline history of atrial fibrillation/flutter, atrial fibrillation/flutter hospitalization rates were 12.5% (46/368) with VASCEPA versus 6.3% (24/383) with placebo (p=0.007).

In 7,428 patients without baseline history of atrial fibrillation/flutter, atrial fibrillation/flutter hospitalization rates were 2.2% with VASCEPA versus 1.6% with placebo (p=0.09).

Other adverse events (AE) of interest:

The rate of treatment-emergent serious adverse events for bleeding was 2.7% in the VASCEPA group versus 2.1% in the placebo group, with a nonsignificant, but trending p-value of 0.06.

A significantly higher incidence of any bleeding occurred with VASCEPA (11.8% versus 9.9%; p=0.006), but as noted above between group differences were not statistically significant for serious bleeding, serious central nervous system bleeding, serious gastrointestinal bleeding, or adjudicated hemorrhagic stroke, and there were no bleeding-associated deaths assessed by investigators as related to VASCEPA.

Mineral oil placebo consideration and analysis

In REDUCE-IT, a placebo containing mineral oil was used to mimic the color and consistency of the drug studied. No strong evidence for biological activity of the same mineral oil was identified in connection with FDA approval of VASCEPA in July 2012 based on the MARINE phase 3 clinical trial, in connection with FDA review of the ANCHOR phase 3 clinical trial, or after several years of quarterly review by the Data Monitoring Committee (DMC) for REDUCE-IT after FDA requested that the DMC periodically assess unblinded lipid data to monitor for signals that the placebo might not be inert. While the DMC noted variation in LDL-C measurements in both arms and that a small physiological effect of mineral oil might be possible, the DMC concluded that it was not possible to determine if the LDL-C increase in the placebo arm was a natural increase over time or due to the mineral oil, and they found no apparent effect on outcomes and considered this small change as unlikely to explain the observed benefit of VASCEPA over placebo.

Each of the three VASCEPA clinical trials, MARINE, ANCHOR and REDUCE-IT, was conducted under a special protocol, or SPA, agreement with FDA in which mineral oil was agreed with FDA as an acceptable placebo.

REDUCE-IT patients represent a population at significant risk for CV events as reflected in the study design that assumed an annual placebo group primary endpoint event rate of 5.9% based on historical data, and as suggested by the observed annualized placebo event rate (5.74%), which remains consistent with historical data for similar at-risk statin-treated patient populations.

As published within the main New England Journal of Medicine presentation of the REDUCE-IT results, at baseline, the median LDL-C was 75.0 mg/dL. The median change in LDL-C was 3.1% (+2.0 mg/dL) for VASCEPA and 10.2% (+7.0 mg/dL) for the mineral oil placebo arm; placebo-corrected median change from baseline of -6.6% (-5.0 mg/dL; p < 0.001). If mineral oil in the placebo might have affected outcomes in some patients, this might have contributed to differences in outcomes between the groups. However, the relatively small differences in LDL-C levels between groups would not likely explain the 25% risk reduction observed with VASCEPA, and a post hoc analysis suggested a similar lower risk regardless of whether there was an increase in LDL-C level among the patients in the placebo group or regardless of the experience of diarrhea while on study. In addition, although open label, Japan EPA Lipid Intervention Study (JELIS) previously demonstrated a 19% risk reduction without a mineral oil placebo.

CONDUCT OF REDUCE-IT AND ANALYSIS AND REVIEW OF REDUCE-IT DATA

FDA has not reviewed and opined on a supplemental new drug application related to REDUCE-IT. FDA has thus not reviewed the information herein or determined whether to approve VASCEPA for use to reduce the risk of major adverse CV events in the REDUCE-IT patient population.*

REDUCE-IT results were first presented at the 2018 Scientific Sessions of the American Heart Association (AHA) on November 10, 2018 in Chicago, Illinois and concurrently published online in The New England Journal of Medicine (NEJM).2,3

REDUCE-IT was sponsored by Amarin Pharma, Inc. and its affiliates and conducted under a special protocol assessment agreement with FDA.

The REDUCE-IT steering committee, consisting of academic physicians, and Amarin representatives developed the protocol and were responsible for the conduct and oversight of the study, and data interpretation.

Further REDUCE-IT data assessment and data release could yield additional useful information to inform greater understanding of the trial outcome:

Further detailed data assessment by Amarin and regulatory authorities will continue and take several months to complete and record

The final evaluation of the totality of the efficacy and safety data from REDUCE-IT may include some or all of the following, as well as other considerations:

New information affecting the degree of treatment benefit on studied endpoints

Study conduct and data robustness, quality, integrity and consistency

Additional safety data considerations and risk/benefit considerations

Consideration of REDUCE-IT results in the context of other clinical studies.

VASCEPA may not be eligible for reimbursement under government healthcare programs (such as Medicare and Medicaid) and certain commercial plans to reduce the risk of major adverse CV events in the REDUCE-IT patient population. We encourage you to check that for yourself.

IMPORTANT INFORMATION FOR HCPs ABOUT CONTINUED UNCERTAINTY AROUND THE BENEFIT, IF ANY, OF LOWERING TG LEVELS AFTER STATIN THERAPY IN PATIENTS WITH HIGH (200-499 mg/dL) TG LEVELS

In REDUCE-IT, CV benefits appeared similar across baseline levels of triglycerides (less than versus greater than or equal to 150 mg/dL or 200 mg/dL).

Additionally, the reduction in major adverse CV events with VASCEPA appeared to occur irrespective of an achieved triglyceride level above or below 150 mg/dL at one year, suggesting that the CV risk reduction was not tied to achieving a more normal triglyceride level.

These observations suggest that at least some of the impact of VASCEPA on the reduction in ischemic events may be explained by metabolic effects other than triglyceride lowering.

VASCEPA is not FDA-approved to lower TG levels in statin-treated patients with mixed dyslipidemia and persistent high (≥200 mg/dL and <500 mg/dL) TG levels due to current uncertainty regarding the benefit, if any, of drug-induced changes in lipid/lipoprotein parameters beyond statin-lowered LDL-C on CV risk among statin-treated patients with residually high TG.

Other CV outcomes trials (ACCORD Lipid, AIM-HIGH, and HPS2-THRIVE), while not designed to test the effect of lowering TG levels in patients with high TG levels after statin therapy, each failed to demonstrate incremental CV benefit of adding a second lipid-altering drug (fenofibrate or formulations of niacin), despite raising high-density lipoprotein cholesterol and reducing TG levels, among statin-treated patients with well-controlled LDL-C.

Other cardiovascular outcomes trials that studied fish oil or mixtures of omega-3 acids that include the omega-3 acid, DHA, have reported negligible impact on cardiovascular events.

No head-to head, randomized, well-controlled studies have been conducted to compare the effects of VASCEPA with other FDA-approved TG-lowering therapies.

POTENTIAL MECHANISMS OF ACTION

Mechanisms responsible for the benefit shown in REDUCE-IT were not included in the study design. Potential mechanisms discussed, include TG reduction, anti‑thrombotic effects, antiplatelet or anticoagulant effects, membrane-stabilizing effects, effects on stabilization and/or regression of coronary plaque and inflammation reduction. More study is needed to determine to what extent, if any, these effects or others may be responsible for the CV risk reduction benefit demonstrated with use of VASCEPA in REDUCE-IT.

FDA-Approved Indication and Limitations of Use for VASCEPA1

VASCEPA® (icosapent ethyl) is indicated as an adjunct to diet to reduce triglyceride (TG) levels in adult patients with severe (≥500 mg/dL) hypertriglyceridemia.

In patients with severe hypertriglyceridemia, the effect of VASCEPA on cardiovascular mortality or morbidity or on the risk of pancreatitis has not been determined.

Please see full Important Safety Information for VASCEPA and Important New Information from the recently completed REDUCE-IT™ cardiovascular outcomes study.
FDA has not reviewed and opined on a supplemental new drug application related to REDUCE-IT. FDA has thus not reviewed the information herein or determined whether to approve VASCEPA for use to reduce the risk of major adverse cardiovascular events in the REDUCE-IT patient population.

Important Safety Information for VASCEPA from FDA-Approved Label

VASCEPA is contraindicated in patients with known hypersensitivity (e.g., anaphylactic reaction) to VASCEPA or any of its components

Use with caution in patients with known hypersensitivity to fish and/or shellfish

In patients with hepatic impairment, monitor ALT and AST levels periodically during therapy

The most common reported adverse reaction (incidence >2% and greater than placebo) was arthralgia (2.3% VASCEPA, 1.0% placebo)

Adverse events may be reported by calling 1-855-VASCEPA or the FDA at 1-800-FDA-1088

IMPORTANT INFORMATION FOR HCPs ABOUT VASCEPA AS AN ADD-ON TO STATINS IN PATIENTS WITH HIGH (200-499 mg/dL) TG LEVELS

Supportive but not conclusive research shows that consumption of EPA and DHA omega-3 fatty acids may reduce the risk of coronary heart disease. VASCEPA should not be taken in place of a healthy diet and lifestyle or statin therapy

The ANCHOR trial demonstrates that VASCEPA lowers TG levels in patients with high (≥200 mg/dL and <500 mg/dL) TG levels not controlled by diet and statin therapy

The reduction in TG observed with VASCEPA was not associated with elevations in LDL-C relative to placebo

VASCEPA is not FDA-approved for the treatment of statin-treated patients with mixed dyslipidemia and high (≥200 mg/dL and <500 mg/dL) TG levels due to current uncertainty regarding the benefit, if any, of drug-induced changes in lipid/lipoprotein parameters beyond statin-lowered LDL-C on cardiovascular risk among statin-treated patients with residually high TG. No prospective study has been conducted to test and support what, if any, benefit exists

Recent cardiovascular outcomes trials (ACCORD Lipid, AIM-HIGH, and HPS2-THRIVE), while not designed to test the effect of lowering TG levels in patients with high TG levels after statin therapy, each failed to demonstrate incremental cardiovascular benefit of adding a second lipid-altering drug (fenofibrate or formulations of niacin), despite raising HDL-C and reducing TG levels, among statin-treated patients with well-controlled LDL-C

VASCEPA is not FDA-approved to reduce the risk of coronary heart disease

The effect of VASCEPA on the risk of cardiovascular mortality and morbidity has not been determined

A cardiovascular outcomes study of VASCEPA designed to evaluate the efficacy of VASCEPA in reducing cardiovascular mortality and morbidity in a high-risk patient population on statin therapy is currently underway (REDUCE-IT)

VASCEPA may not be eligible for reimbursement under government healthcare programs (such as Medicare and Medicaid) to reduce the risk of coronary heart disease or for treatment of statin-treated patients with mixed dyslipidemia and high (≥200 mg/dL and <500 mg/dL) TG levels. We encourage you to check that for yourself

The ANCHOR trial was sponsored by Amarin Pharma, Inc. and its affiliates

VASCEPA significantly reduced TG, non–HDL-C, Apo B, VLDL-C, TC, and HDL-C levels from baseline relative to placebo. The reduction in TG observed with VASCEPA was not associated with elevations in LDL-C relative to placebo.

The effect of VASCEPA on cardiovascular mortality and morbidity in patients with mixed dyslipidemia has not been determined.

Important Information for Healthcare Professionals on Inflammatory Markers3,4

With the exception of Lp-PLA2, a secondary endpoint, all of the other inflammatory markers were exploratory endpoints

In the ANCHOR and MARINE trials, VASCEPA 4 g/d significantly reduced Lp-PLA2 and hsCRP levels from baseline relative to placebo in each of the respective groups of patients with hypertriglyceridemia studied. In the ANCHOR trial, VASCEPA 4 g/d significantly reduced Ox-LDL levels from baseline relative to placebo

In the ANCHOR trial,

Lp-PLA2 and hsCRP were measured in ≥93% of randomized patients

ICAM-1, Ox-LDL, and IL-6 were measured in the first 240 of 702 (34.2%) of randomized patients (or approximately 80 patients per each of the three treatment arms)

In the MARINE trial, inflammatory markers were measured in ≥183 of 229 (≥80%) of randomized patients (or ≥60 patients per each of the three treatment arms)

hsCRP is an acute-phase reactant and has high intra-individual variability

Therefore, a single test for hsCRP, as was performed at each timepoint of the ANCHOR and MARINE trials, may not accurately reflect an individual patient’s basal or on-treatment hsCRP levels

Repeat measurement may be required to firmly establish an individual’s basal hsCRP concentration, as well as to accurately understand treatment-induced changes in hsCRP

ANCHOR Inflammatory Markers: Response to the Addition of VASCEPA to Ongoing Statin Therapy in Patients with High Triglyceride Levels (≥200 mg/dL and <500 mg/dL)

Only subjects with non-missing baseline and week 12 values are included. P values for Lp-PLA2, a secondary endpoint, were adjusted for multiple comparisons; all other endpoints are exploratory. The n’s represent the number of subjects with marker samples tested in the VASCEPA 4 g/day + statin and placebo + statin treatment arms, respectively.

Only subjects with non-missing baseline and week 12 values are included. P values for Lp-PLA2, a secondary endpoint, were adjusted for multiple comparisons; all other endpoints are exploratory. The n’s represent the number of subjects with marker samples tested in the VASCEPA 4 g/day and placebo treatment arms, respectively.

VASCEPA is not FDA-approved to reduce the inflammatory biomarkers discussed in this document

The effects of VASCEPA on inflammatory biomarkers have not been approved for inclusion in FDA-approved labeling of VASCEPA

Additional trials are needed to evaluate the CV benefit, if any, of reducing inflammatory biomarkers with VASCEPA

Despite the putative cardio-protective effects reported in earlier literature for niacin on markers including C-reactive protein (CRP), Lp-PLA2, and other inflammatory biomarkers, a beneficial effect on major adverse cardiovascular events (MACE) was not observed for niacin in the AIM-HIGH and HPS2-THRIVE trials when studied in patients with well controlled LDL-C levels on statin therapy. Therefore, a non-statin lipid altering drug effect on such inflammatory biomarkers may not translate into a reduced risk for MACE when used in combination with statin therapy

Lp-PLA2 has been evaluated in two large CV outcome trials with an investigational agent that inhibits Lp-PLA2 activity. One study showed no impact on CV events in patients hospitalized for acute coronary syndrome [O’Donoghue et al., JAMA 2014]. The other study showed no impact on CV events in patients with chronic coronary disease (prior myocardial infarction, prior revascularization, or multivessel coronary disease) [STABILITY Investigators, NEJM 2014]. Additionally, a genetic study found that variants that reduce Lp-PLA2 activity to a degree similar to activity associated with darapladib, an Lp-PLA2 inhibitor, had no effect on the risk of coronary heart disease [Polfus et al., NEJM 2015]

hsCRP was evaluated in a CV outcomes trial that demonstrated that high-intensity statin therapy reduced CV risk in individuals with hsCRP ≥2.0 mg/L, LDL-C <130 mg/dL, and one additional CV risk factor, however, the study was not designed to evaluate whether statin therapy would still reduce atherosclerotic cardiovascular disease (ASCVD) risk in individuals with CRP <2.0 mg/L and the same 10-year cardiovascular risk [Ridker et al., NEJM 2008; Stone et al., Circulation 2014]. Additionally, this CV outcomes trial, called Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER), was not designed to evaluate whether treatment guided by risk based on hsCRP levels would improve health outcomes [Stone et al., Circulation 2014]. Statins are likely to provide benefit without regard to elevated hsCRP levels [Yousuf et al., JACC 2013]

It is unclear to what degree hsCRP reduction contributed to the results from the JUPITER trial

It is unknown whether results similar to those from the JUPITER trial could be achieved with other statins or with adjuncts to statin therapy

JUPITER did not use any adjuncts to statin therapy to reduce lipids or inflammatory biomarkers

JUPITER was not a study of patients with high median triglyceride levels (≥200 mg/dL) at baseline

Both hsCRP and IL-6 were evaluated in the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial with the use of canakinumab, a monoclonal antibody that neutralizes IL-1β, as secondary prevention in patients (N=10,061) with a previous myocardial infarction and an elevated level of hsCRP [Ridker et al., NEJM 2017]. Over 90% of patients also received statin therapy. The effect of VASCEPA, if any, on IL-1β has not been studied

The CANTOS trial did show a CV relative risk reduction (15%) in patients with a prior myocardial infarction and an hsCRP level of 2 mg/L with the 150-mg dose, but not with the other doses studied

In CANTOS, at 48 months, there were no significant reductions from baseline in LDL-C or HDL-C and a 4%-5% median increase in TGs from baseline

Matsuzaki et al. 2009: An additional JELIS sub-analysis that assessed the incidence of secondary major cardiovascular events in patients with established CAD7

JELIS was supported by grants from the manufacturer of the product, Mochida Pharmaceutical Co Ltd, Tokyo, Japan.

The product studied in JELIS and VASCEPA® (icosapent ethyl) capsules

The product studied in JELIS and VASCEPA, are highly similar based on a US Food and Drug Administration (FDA) review of both a comprehensive analytical comparison and published reports on each product’s content. Each product is highly purified EPA. The product studied in JELIS is not available in the United States.

The highly purified EPA studied in JELIS was administered at 1.8 grams/day (g/d). VASCEPA at 4 g/d is an FDA-approved product indicated for a different use than that investigated in JELIS (see VASCEPA (icosapent ethyl) Indication and Limitations of Use above). The effect of VASCEPA on cardiovascular mortality and morbidity has not been determined. VASCEPA 4 g/d is under clinical investigation to evaluate its potential in reducing cardiovascular mortality and morbidity in a combined primary and secondary prevention (high-risk) patient population receiving statin therapy (see Ongoing cardiovascular outcomes study of VASCEPA in statin-treated patients below).

Important Information for healthcare professionals about JELIS

JELIS provides supportive but not conclusive data that EPA drug therapy may reduce major coronary events

JELIS reached its primary endpoint in the combined primary and secondary prevention population showing a 19% relative risk reduction in major coronary events in statin-treated patients with hypercholesterolemia in Japan

The main component contributing to the primary endpoint results in JELIS summarized herein was unstable angina involving hospital treatment, which is a more subjective endpoint result than, for example, objective major adverse cardiovascular event endpoints (e.g., heart attack, stroke, or cardiovascular death)

A subjective endpoint, such as unstable angina, may be particularly unreliable in an open-label trial, such as JELIS, where patients and healthcare professionals are making decisions regarding hospitalizations

JELIS results cannot be generalized to other populations

Subjects in JELIS were limited to Japanese adults

The average dietary intake of fish in Japan is about 5 times higher than that in other countries

Baseline blood EPA levels in JELIS before pharmacotherapy with 1.8 g/d of EPA were higher than those recorded in the US population

Subjects in JELIS received a low dose of statin therapy based on then-current Japanese treatment guidelines that may be considered inadequate under current guidelines in the United States

FDA determined that JELIS results could not be used as support for or against the use of TG levels as a surrogate for cardiovascular risk reduction

In the primary endpoint analysis, median baseline TG levels were not high (153 mg/dL [1.73 mmol/L])

Assessment of the TG-lowering benefits of EPA therapy in JELIS is complicated by the small number of subjects with high median TG levels (≥200 mg/dL) at baseline prior to statin treatment

A statin run-in or stabilization period prior to randomization to EPA would have likely further reduced the baseline median TG level

Patients treated with EPA and statin in JELIS achieved TG levels that were only 5% lower, on average, than those achieved among patients treated with statin alone; however, the reduction in cardiovascular risk in the primary endpoint analysis was 19% [Yokoyama]

Likewise, within the primary and secondary prevention sub-analyses, TG levels were lowered only 5% on average in the EPA plus statin group compared with the statin alone group; however, the relative risk reduction was

53% in the primary prevention population with elevated TG and low HDL-C levels [Saito]

23% in the secondary prevention population with established CAD [Matsuzaki]

These large differences in magnitude between TG reduction and risk reduction in JELIS suggest that the effects of EPA on TG levels alone may not be responsible for, or predict, the observed differences in cardiovascular events between treatment groups in JELIS

A nonstatin lipid-altering drug’s effects on biomarkers may not translate into a reduced cardiovascular risk when used in combination with statin therapy (see Important Information for HCPs about VASCEPA as an add-on to statins in patients with high [200-499 mg/dL] TG levels)

It is possible that the putative cardioprotective effects of EPA observed in JELIS are due not to a single mode of action, such as TG lowering, but rather to multiple mechanisms working together

Further study is needed to determine the clinical benefit, if any, of EPA therapy in statin-treated patients with elevated TG levels (see Ongoing cardiovascular outcomes study of VASCEPA in statin-treated patients below)

Limitations of subpopulation analyses

JELIS reached its primary endpoint in the combined primary and secondary prevention population

JELIS was not powered to evaluate primary and secondary prevention populations individually or those explored in the Saito and Matsuzaki publications

Major coronary events: JELIS and sub-analyses

Adapted from Yokoyama et al, Figure 3: Estimated hazard ratios of clinical endpoints stratified by prevention stratum; Saito et al, Figure 3: Effects of EPA on the incidence of MCE for the high TG/low HDL-C group; Matsuzaki et al, Figure 2a: Kaplan-Meier estimates of the incidence of the primary endpoint of coronary events occurring in the group of all patients.

Major Coronary Events

EPA + Statin

Statin (Control)

P value

HR (95% Confidence Interval)

Yokoyama et al.

Total population
(N=18,645)

2.8%

3.5%

0.011

0.81 (0.69-0.95)

Primary prevention
(n=14,981)

1.4%

1.7%

0.132

0.82 (0.63-1.06)

Secondary prevention
(n=3,664)

8.7%

10.7%

0.048

0.81 (0.66-1.00)

Saito et al.
High TG (≥150 mg/dL)/low HDL-C (<40 mg/dL)
(n=957)*

3.3% for pooled treatment arms; event rates were not reported for each arm

0.043

0.47 (0.23-0.98)

Matsuzaki et al.

CAD
(n=3,664)†

8.7%

10.7%

0.017

0.77 (0.63-0.96)

HR, hazard ratio.

*There was no suggestion of a difference in treatment effect between TG levels of ≥151 mg/dL (HR, 0.84; 95% Confidence Interval, 0.68-1.04) and TG levels of <151 mg/dL (HR, 0.79; 95% Confidence Interval, 0.61-1.02) when HDL-C is not considered (interaction P=0.75).

†When JELIS was conducted (over the period of 1996-2004), cholesterol management was not as aggressive as it is today for someone with established CAD. In addition, there was likely less use of antiplatelet/anticoagulant agents for someone with established CAD as there is in medical practice today.

The rate of discontinuation due to treatment-related adverse effects was 11.7% in the EPA group and 7.2% in the control group

Other cardiovascular outcomes trials in the omega-3 class have reported negligible impact on cardiovascular events

JELIS is the only cardiovascular outcomes trial that has examined the effects of EPA (1.8 g/d) plus statin vs statin alone. The 12-week end-of-treatment blood levels after 4 g/d of EPA in an American population achieved approximately the same end-of-treatment blood levels of EPA observed in the Japanese population studied in JELIS.9 The clinical relevance of EPA blood levels on cardiovascular outcomes has not been determined.

Following JELIS and GISSI-P (Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto miocardico-Prevenzione),10 randomized placebo-controlled trials have failed to confirm definitive cardiovascular benefit with similarly low (<2 g/d) doses of omega-3 fatty acid mixtures. GISSI-P is an open-label outcomes trial (1 g omega-3 fatty acid mixture), conducted in Italy, that supported the hypothesis that omega-3 fatty acids likely exert their cardioprotective effects through nonlipid-mediated mechanisms. But, in GISSI-P, only ≈5% of patients were receiving statins at baseline compared with >40%-50% in more recent, similarly low-dose omega-3 trials that failed to confirm benefit. GISSI-P did not suggest an effect on the incidence of nonfatal cardiovascular events and the effects of omega-3 fatty acids on lipids, including serum TGs, were negligible.

The omega-3 fatty acid mixtures studied in such other outcomes trials were primarily comprised of EPA and docosahexaenoic acid (DHA) (typically, approximately 900 mg total per 1 gram capsule) and also typically included a number of other omega-3 and omega-6 acids, as well as other constituents. No head-to-head cardiovascular outcomes study of EPA vs a mixture of omega-3 acids has been conducted. No cardiovascular outcomes trial has been completed with sufficient power to prospectively evaluate the effect of EPA or omega-3 fatty acid mixtures in statin-treated patients, either with high TG levels (≥200 mg/dL) or with both high TG and low HDL-C levels.

The encouraging results of JELIS contributed to the justification to investigate the potential of VASCEPA to reduce cardiovascular risk. A cardiovascular outcomes study of VASCEPA designed to evaluate the efficacy of 4 g/d of VASCEPA in reducing cardiovascular mortality and morbidity in a high-risk patient population on statin therapy is currently underway (REDUCE-IT). The sponsor of REDUCE-IT, Amarin Pharma, Inc., and the FDA are strongly aligned in recognizing the importance of continuing to collaborate to complete REDUCE-IT so that a definitive answer may be provided to answer the question of whether VASCEPA, in combination with a statin, results in reduction of cardiovascular risk over a statin alone.

Participants in the clinical investigation of VASCEPA currently underway (REDUCE-IT) should not be advised to use VASCEPA in place of participation in that study. VASCEPA should not be taken in place of a healthy diet and lifestyle or statin therapy.

VASCEPA may not be eligible for reimbursement under government healthcare programs (such as Medicare and Medicaid) to reduce the risk of coronary heart disease or for treatment of statin-treated patients with high (≥200 mg/dL and <500 mg/dL) TG levels. We encourage you to check that for yourself.

These publications are provided to you by Amarin Pharma, Inc., the manufacturer of VASCEPA.

This website, Vascepa.com, Vascepasavings.com, and the corporation's website, amarincorp.com, are the only company-sanctioned websites pertaining to the Amarin group of companies or its product, VASCEPA® (icosapent ethyl) capsules. The Amarin group of companies is not responsible for false or misleading materials contained on other non–Amarin-controlled websites or other social media sites.